ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1978, p. 958-964
0066-4804/78/0013-0958$02.00/0
Vol. 13, No.6 Printed in U.S.A.
Copyright © 1978 American Society for Microbiology
Infection in Acute Leukemia Patients Receiving Oral Nonabsorbable Antibiotics DAVIS M. HAHN, STEPHEN C. SCHIMPFF,* CLARENCE L. FORTNER, A. COLLIER SMYTH, VIOLA MAE YOUNG, AND PETER H. WIERNIK Baltimore Cancer Research Center, National Cancer Institute at the University of Maryland Hospital, Baltimore, Maryland 21201 Received for publication 16 December 1977
During a 20-month period all acute nonlymphocytic patients (87 patient trials) receiving cytotoxic chemotherapy were placed on an oral nonabsorbable antibiotic regimen consisting of gentamicin, vancomycin, and nystatin in addition to an intensive program of infection prevention aimed at reducing exogenously acquired and body-surface potential pathogens. Although side effects of anorexia, diarrhea, and nausea were common, gentamicin-vancomycin-nystatin was ingested 80% of the study time. Microbial growth in gingival and rectal cultures was substantially reduced. The incidence of bacteremias and other serious infections was low. Pseudomonas aeruginosa, other gram-negative bacilli, and Candida species caused few infections along the alimentary canal, whereas infections of the skin (especially Staphylococcus aureus) were not reduced compared with those occurring in former years. A total of the 104 acquired gram-negative bacilli were gentamicin resistant; 5 subsequently caused infection. Thus, despite certain definite drawbacks, the use of oral nonabsorbable antibiotics to suppress alimentary tract microbial flora in combination with other infection prevention techniques in granulocytopenic cancer patients has proven feasible and tolerable and has been associated with a low order of life-threatening infections.
Infection remains a major threat to the granulocytopenic patient with acute nonlymphocytic leukemia (ANLL). Infectious death is common and, until recent years, 25% or more patients died before an adequate trial of chemotherapy could be completed (10, 15, 21). Many infections have been associated with the alimentary tract (pharyngitis, esophagitis, colitis, and perianal
In a prospective randomized trial from July 1970 to June 1973 (19) at the Baltimore Cancer Research Center, alimentary tract flora suppression with oral nonabsorbable antibiotics decreased the number of total infections, bacteremias, pneumonias, perirectal lesions, urinary tract infections, and pharyngitis compared with those of the control group. The addition of reverse isolation with air filtration in a laminar air-flow room to oral nonabsorbable antibiotics showed an even greater degree of infection reduction (19). As a result of these data, since only one laminar air-flow room was available, all patients with ANLL admitted to this center since August 1973 have had oral nonabsorbable antibiotics prescribed in conjunction with an overall program of infection prevention. In this communication we describe the infectious complications that occurred in the 70 consecutive patients admitted since the oral nonabsorbable antibiotic regimen became a standard mode of therapy.
lesions) with most being caused by flora colonizing the alimentary tract, especially Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Candida species (3, 9, 10, 15, 21). One-half or more of these pathogens have been found to be acquired during the course of hospitalization (21). Attempts at infection prevention have included procedures to reduce acquisition, e.g., reverse isolation in laminar air-flow rooms, and alimentary tract microbial flora suppression, e.g., oral nonabsorbable antibiotics. Infection rates are markedly reduced when these techniques are used together (4-8, 12, 13, 16, 19, 24). Some investigators (12, 13, 17, 19, 23) have found MATERIALS AND METHODS substantial infection reduction with the use of oral nonabsorbable antibiotics alone, whereas Patient population. From August 1973 to April others have not (15, 18, 24). Likewise, isolation 1975, all patients with the diagnosis of ANLL and alone appeared useful in two trials (6, 24). The being treated with cytotoxic induction chemotherapy were prescribed the oral nonabsorbable antibiotic regsubject has been reviewed recently (14, 18). 958
VOL. 13, 1978
INFECTION IN ACUTE LEUKEMIA PATIENTS
imen usually several days before initiation of antileukemic therapy. On-study time. On-study time was from the time of admission until the patient achieved a complete hematological remission with return of granulocyte count to 1,000/mm3, or until death. Classification of infection. Based on clinical course and microbiological data, infections were classified (20, 21) as one of the following: microbiologically documented-with and without bacteremia (site and pathogen defined); clinically documented (site defined but no pathogen); and possible infection (equivocal). Oral nonabsorbable antibiotic regimen. The oral regimen, which was given every 4 h, consisted of 200 mg of gentamicin liquid, 500 mg of vancomycin liquid, 4 million U of nystatin tablets, and 1 million U of nystatin liquid (GVN). The patient's compliance was carefully monitored. Patients were frequently reminded about the importance of GVN ingestion and the risks of discontinuing this regimen. Infection prevention. Intravenous and urinary catheters were used only in the setting of shock and lower urinary tract obstruction. Butterfly needles were changed every 48 h; all intravenous bottles and tubes were changed every 24 h. Patients and staff were separately and repeatedly educated regarding good personal hygiene. The patients were instructed in oral care and, unlike previous years (19), all patients were placed on a cooked-food diet. Reverse isolation was utilized during seven patient trials. Microbiological surveillance. Surveillance cultures of the nose, gingiva, axilla, and rectum were obtained twice a week during hospitalization (19). Morphologically distinct colonies were identified as to species, and antimicrobial susceptibility tests by the Kirby-Bauer method (2) were done initially for each gram-negative bacillus and S. aureus. These were repeated intermittently to check for development of resistance to the oral antibiotics. Hospital setting. The Baltimore Cancer Research Center was housed at the Baltimore U.S. Public Health Service Hospital until June 1974, when it was transferred to the University of Maryland Hospital. In both locations, the inpatient area, outpatient clinic, and support laboratories were maintained on one floor. Most patients spent part of their on-study time as outpatients being followed daily. Antileukemic therapy. Therapy for initial induction or first relapse was usually daunorubicin or a combination of daunorubicin, cytosine arabinoside, thioguanine, and pyrimethamine (23). Patients refractory to this therapy were then treated with various other chemotherapeutic agents. Antileukemic therapy consisted of initial induction therapy, 52 patient trials; treatment for first relapse, 23 patient trials; treatment for second relapse, 8 patient trials; and treatment for third relapse, 4 patient trials. Empiric antibiotic therapy for suspected infections. After completion of appropriate diagnostic procedures, granulocytopenic, febrile patients were begun on an empiric combination of two of three or all three of the following intravenous antibiotics: carbenicillin (or ticarcillin), cephalothin, and/or gentamicin (8). Antibiotic adjustments were made when indicated by clinical or microbiological data or when renal failure was present.
959
Statistical method. Incidence of infection was computed as infections per 1,000 days on-study. The Fisher exact test with two-tail distribution was used for comparing proportions.
RESULTS Patient population. There were 87 consecutive patient trials among 70 patients (53 treated once, 17 treated twice). Ages ranged from 16 to 79 years with a mean of 45 and median of 48. The mean on-study time was 94 days per patient trial (median 64 days, range 6 to 483 days). Patients were granulocytopenic 71% of the onstudy time and had an absolute granulocyte count of 500 PMN per mm3. Ninety-two percent of bacteremias (24/26) and 70% of microbiologically documented severe infections occurred when the PMN count was 100 per mm3. The vast majority of P. aeruginosa (18/22), other gram-negative organisms (21/30), Candida sp. (8/10), and Aspergillus infections (6/8) occurred when the PMN count was
0066-4804/78/0013-0958$02.00/0
Vol. 13, No.6 Printed in U.S.A.
Copyright © 1978 American Society for Microbiology
Infection in Acute Leukemia Patients Receiving Oral Nonabsorbable Antibiotics DAVIS M. HAHN, STEPHEN C. SCHIMPFF,* CLARENCE L. FORTNER, A. COLLIER SMYTH, VIOLA MAE YOUNG, AND PETER H. WIERNIK Baltimore Cancer Research Center, National Cancer Institute at the University of Maryland Hospital, Baltimore, Maryland 21201 Received for publication 16 December 1977
During a 20-month period all acute nonlymphocytic patients (87 patient trials) receiving cytotoxic chemotherapy were placed on an oral nonabsorbable antibiotic regimen consisting of gentamicin, vancomycin, and nystatin in addition to an intensive program of infection prevention aimed at reducing exogenously acquired and body-surface potential pathogens. Although side effects of anorexia, diarrhea, and nausea were common, gentamicin-vancomycin-nystatin was ingested 80% of the study time. Microbial growth in gingival and rectal cultures was substantially reduced. The incidence of bacteremias and other serious infections was low. Pseudomonas aeruginosa, other gram-negative bacilli, and Candida species caused few infections along the alimentary canal, whereas infections of the skin (especially Staphylococcus aureus) were not reduced compared with those occurring in former years. A total of the 104 acquired gram-negative bacilli were gentamicin resistant; 5 subsequently caused infection. Thus, despite certain definite drawbacks, the use of oral nonabsorbable antibiotics to suppress alimentary tract microbial flora in combination with other infection prevention techniques in granulocytopenic cancer patients has proven feasible and tolerable and has been associated with a low order of life-threatening infections.
Infection remains a major threat to the granulocytopenic patient with acute nonlymphocytic leukemia (ANLL). Infectious death is common and, until recent years, 25% or more patients died before an adequate trial of chemotherapy could be completed (10, 15, 21). Many infections have been associated with the alimentary tract (pharyngitis, esophagitis, colitis, and perianal
In a prospective randomized trial from July 1970 to June 1973 (19) at the Baltimore Cancer Research Center, alimentary tract flora suppression with oral nonabsorbable antibiotics decreased the number of total infections, bacteremias, pneumonias, perirectal lesions, urinary tract infections, and pharyngitis compared with those of the control group. The addition of reverse isolation with air filtration in a laminar air-flow room to oral nonabsorbable antibiotics showed an even greater degree of infection reduction (19). As a result of these data, since only one laminar air-flow room was available, all patients with ANLL admitted to this center since August 1973 have had oral nonabsorbable antibiotics prescribed in conjunction with an overall program of infection prevention. In this communication we describe the infectious complications that occurred in the 70 consecutive patients admitted since the oral nonabsorbable antibiotic regimen became a standard mode of therapy.
lesions) with most being caused by flora colonizing the alimentary tract, especially Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Candida species (3, 9, 10, 15, 21). One-half or more of these pathogens have been found to be acquired during the course of hospitalization (21). Attempts at infection prevention have included procedures to reduce acquisition, e.g., reverse isolation in laminar air-flow rooms, and alimentary tract microbial flora suppression, e.g., oral nonabsorbable antibiotics. Infection rates are markedly reduced when these techniques are used together (4-8, 12, 13, 16, 19, 24). Some investigators (12, 13, 17, 19, 23) have found MATERIALS AND METHODS substantial infection reduction with the use of oral nonabsorbable antibiotics alone, whereas Patient population. From August 1973 to April others have not (15, 18, 24). Likewise, isolation 1975, all patients with the diagnosis of ANLL and alone appeared useful in two trials (6, 24). The being treated with cytotoxic induction chemotherapy were prescribed the oral nonabsorbable antibiotic regsubject has been reviewed recently (14, 18). 958
VOL. 13, 1978
INFECTION IN ACUTE LEUKEMIA PATIENTS
imen usually several days before initiation of antileukemic therapy. On-study time. On-study time was from the time of admission until the patient achieved a complete hematological remission with return of granulocyte count to 1,000/mm3, or until death. Classification of infection. Based on clinical course and microbiological data, infections were classified (20, 21) as one of the following: microbiologically documented-with and without bacteremia (site and pathogen defined); clinically documented (site defined but no pathogen); and possible infection (equivocal). Oral nonabsorbable antibiotic regimen. The oral regimen, which was given every 4 h, consisted of 200 mg of gentamicin liquid, 500 mg of vancomycin liquid, 4 million U of nystatin tablets, and 1 million U of nystatin liquid (GVN). The patient's compliance was carefully monitored. Patients were frequently reminded about the importance of GVN ingestion and the risks of discontinuing this regimen. Infection prevention. Intravenous and urinary catheters were used only in the setting of shock and lower urinary tract obstruction. Butterfly needles were changed every 48 h; all intravenous bottles and tubes were changed every 24 h. Patients and staff were separately and repeatedly educated regarding good personal hygiene. The patients were instructed in oral care and, unlike previous years (19), all patients were placed on a cooked-food diet. Reverse isolation was utilized during seven patient trials. Microbiological surveillance. Surveillance cultures of the nose, gingiva, axilla, and rectum were obtained twice a week during hospitalization (19). Morphologically distinct colonies were identified as to species, and antimicrobial susceptibility tests by the Kirby-Bauer method (2) were done initially for each gram-negative bacillus and S. aureus. These were repeated intermittently to check for development of resistance to the oral antibiotics. Hospital setting. The Baltimore Cancer Research Center was housed at the Baltimore U.S. Public Health Service Hospital until June 1974, when it was transferred to the University of Maryland Hospital. In both locations, the inpatient area, outpatient clinic, and support laboratories were maintained on one floor. Most patients spent part of their on-study time as outpatients being followed daily. Antileukemic therapy. Therapy for initial induction or first relapse was usually daunorubicin or a combination of daunorubicin, cytosine arabinoside, thioguanine, and pyrimethamine (23). Patients refractory to this therapy were then treated with various other chemotherapeutic agents. Antileukemic therapy consisted of initial induction therapy, 52 patient trials; treatment for first relapse, 23 patient trials; treatment for second relapse, 8 patient trials; and treatment for third relapse, 4 patient trials. Empiric antibiotic therapy for suspected infections. After completion of appropriate diagnostic procedures, granulocytopenic, febrile patients were begun on an empiric combination of two of three or all three of the following intravenous antibiotics: carbenicillin (or ticarcillin), cephalothin, and/or gentamicin (8). Antibiotic adjustments were made when indicated by clinical or microbiological data or when renal failure was present.
959
Statistical method. Incidence of infection was computed as infections per 1,000 days on-study. The Fisher exact test with two-tail distribution was used for comparing proportions.
RESULTS Patient population. There were 87 consecutive patient trials among 70 patients (53 treated once, 17 treated twice). Ages ranged from 16 to 79 years with a mean of 45 and median of 48. The mean on-study time was 94 days per patient trial (median 64 days, range 6 to 483 days). Patients were granulocytopenic 71% of the onstudy time and had an absolute granulocyte count of 500 PMN per mm3. Ninety-two percent of bacteremias (24/26) and 70% of microbiologically documented severe infections occurred when the PMN count was 100 per mm3. The vast majority of P. aeruginosa (18/22), other gram-negative organisms (21/30), Candida sp. (8/10), and Aspergillus infections (6/8) occurred when the PMN count was
